Publications by authors named "Mauri A Kostiainen"

95 Publications

Neonatal Fc receptor-targeted lignin-encapsulated porous silicon nanoparticles for enhanced cellular interactions and insulin permeation across the intestinal epithelium.

Bioact Mater 2022 Mar 10;9:299-315. Epub 2021 Aug 10.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland.

Oral insulin delivery could change the life of millions of diabetic patients as an effective, safe, easy-to-use, and affordable alternative to insulin injections, known by an inherently thwarted patient compliance. Here, we designed a multistage nanoparticle (NP) system capable of circumventing the biological barriers that lead to poor drug absorption and bioavailability after oral administration. The nanosystem consists of an insulin-loaded porous silicon NP encapsulated into a pH-responsive lignin matrix, and surface-functionalized with the Fc fragment of immunoglobulin G, which acts as a targeting ligand for the neonatal Fc receptor (FcRn). The developed NPs presented small size (211 ± 1 nm) and narrow size distribution. The NPs remained intact in stomach and intestinal pH conditions, releasing the drug exclusively at pH 7.4, which mimics blood circulation. This formulation showed to be highly cytocompatible, and surface plasmon resonance studies demonstrated that FcRn-targeted NPs present higher capacity to interact and being internalized by the Caco-2 cells, which express FcRn, as demonstrated by Western blot. Ultimately, permeability studies showed that Fc-functionalized NPs induced an increase in the amount of insulin that permeated across a Caco-2/HT29-MTX co-culture model, showing apparent permeability coefficients ( ) of 2.37 × 10 cm/s, over the 1.66 × 10 cm/s observed for their non-functionalized counterparts. Overall, these results demonstrate the potential of these NPs for oral delivery of anti-diabetic drugs.
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http://dx.doi.org/10.1016/j.bioactmat.2021.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586719PMC
March 2022

Polyelectrolyte Encapsulation and Confinement within Protein Cage-Inspired Nanocompartments.

Pharmaceutics 2021 Sep 24;13(10). Epub 2021 Sep 24.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, 00076 Aalto, Finland.

Protein cages are nanocompartments with a well-defined structure and monodisperse size. They are composed of several individual subunits and can be categorized as viral and non-viral protein cages. Native viral cages often exhibit a cationic interior, which binds the anionic nucleic acid genome through electrostatic interactions leading to efficient encapsulation. Non-viral cages can carry various cargo, ranging from small molecules to inorganic nanoparticles. Both cage types can be functionalized at targeted locations through genetic engineering or chemical modification to entrap materials through interactions that are inaccessible to wild-type cages. Moreover, the limited number of constitutional subunits ease the modification efforts, because a single modification on the subunit can lead to multiple functional sites on the cage surface. Increasing efforts have also been dedicated to the assembly of protein cage-mimicking structures or templated protein coatings. This review focuses on native and modified protein cages that have been used to encapsulate and package polyelectrolyte cargos and on the electrostatic interactions that are the driving force for the assembly of such structures. Selective encapsulation can protect the payload from the surroundings, shield the potential toxicity or even enhance the intended performance of the payload, which is appealing in drug or gene delivery and imaging.
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http://dx.doi.org/10.3390/pharmaceutics13101551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537137PMC
September 2021

Prospective Cancer Therapies Using Stimuli-Responsive DNA Nanostructures.

Macromol Biosci 2021 Dec 13;21(12):e2100272. Epub 2021 Oct 13.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16100, Aalto, 00076, Finland.

Nanostructures based on DNA self-assembly present an innovative way to address the increasing need for target-specific delivery of therapeutic molecules. Currently, most of the chemotherapeutics being used in clinical practice have undesired and exceedingly high off-target toxicity. This is a challenge in particular for small molecules, and hence, developing robust and effective methods to lower these side effects and enhance the antitumor activity is of paramount importance. Prospectively, these issues could be tackled with the help of DNA nanotechnology, which provides a route for the fabrication of custom, biocompatible, and multimodal structures, which can, to some extent, resist nuclease degradation and survive in the cellular environment. Similar to widely employed liposomal products, the DNA nanostructures (DNs) are loaded with selected drugs, and then by employing a specific stimulus, the payload can be released at its target region. This review explores several strategies and triggers to achieve targeted delivery of DNs. Notably, different modalities are explained through which DNs can interact with their respective targets as well as how structural changes triggered by external stimuli can be used to achieve the display or release of the cargo. Furthermore, the prospects and challenges of this technology are highlighted.
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http://dx.doi.org/10.1002/mabi.202100272DOI Listing
December 2021

Hybrid Nanoassemblies from Viruses and DNA Nanostructures.

Nanomaterials (Basel) 2021 May 27;11(6). Epub 2021 May 27.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16100, 00076 Aalto, Finland.

Viruses are among the most intriguing nanostructures found in nature. Their atomically precise shapes and unique biological properties, especially in protecting and transferring genetic information, have enabled a plethora of biomedical applications. On the other hand, structural DNA nanotechnology has recently emerged as a highly useful tool to create programmable nanoscale structures. They can be extended to user defined devices to exhibit a wide range of static, as well as dynamic functions. In this review, we feature the recent development of virus-DNA hybrid materials. Such structures exhibit the best features of both worlds by combining the biological properties of viruses with the highly controlled assembly properties of DNA. We present how the DNA shapes can act as "structured" genomic material and direct the formation of virus capsid proteins or be encapsulated inside symmetrical capsids. Tobacco mosaic virus-DNA hybrids are discussed as the examples of dynamic systems and directed formation of conjugates. Finally, we highlight virus-mimicking approaches based on lipid- and protein-coated DNA structures that may elicit enhanced stability, immunocompatibility and delivery properties. This development also paves the way for DNA-based vaccines as the programmable nano-objects can be used for controlling immune cell activation.
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http://dx.doi.org/10.3390/nano11061413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228324PMC
May 2021

Challenges in Synthesis and Analysis of Asymmetrically Grafted Cellulose Nanocrystals via Atom Transfer Radical Polymerization.

Biomacromolecules 2021 06 1;22(6):2702-2717. Epub 2021 Jun 1.

Materials Chemistry Division, Chemistry Department, University of Helsinki, A.I. Virtasen aukio 1, FI-00560 Helsinki, Finland.

When cellulose nanocrystals (CNCs) are isolated from cellulose microfibrils, the parallel arrangement of the cellulose chains in the crystalline domains is retained so that all reducing end-groups (REGs) point to one crystallite end. This permits the selective chemical modification of one end of the CNCs. In this study, two reaction pathways are compared to selectively attach atom-transfer radical polymerization (ATRP) initiators to the REGs of CNCs, using reductive amination. This modification further enabled the site-specific grafting of the anionic polyelectrolyte poly(sodium 4-styrenesulfonate) (PSS) from the CNCs. Different analytical methods, including colorimetry and solution-state NMR analysis, were combined to confirm the REG-modification with ATRP-initiators and PSS. The achieved grafting yield was low due to either a limited conversion of the CNC REGs or side reactions on the polymerization initiator during the reductive amination. The end-tethered CNCs were easy to redisperse in water after freeze-drying, and the shear birefringence of colloidal suspensions is maintained after this process.
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http://dx.doi.org/10.1021/acs.biomac.1c00392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382247PMC
June 2021

A Janus-Type Phthalocyanine for the Assembly of Photoactive DNA Origami Coatings.

Bioconjug Chem 2021 06 24;32(6):1123-1129. Epub 2021 May 24.

Department of Bioproducts and Biosystems, Aalto University, Kemistintie 1, 02150 Espoo, Finland.

Design and synthesis of novel photosensitizer architectures is a key step toward new multifunctional molecular materials. Photoactive Janus-type molecules provide interesting building blocks for such systems by presenting two well-defined chemical functionalities that can be utilized orthogonally. Herein a multifunctional phthalocyanine is reported, bearing a bulky and positively charged moiety that hinders their aggregation while providing the ability to adhere on DNA origami nanostructures via reversible electrostatic interactions. On the other hand, triethylene glycol moieties render a water-soluble and chemically inert corona that can stabilize the structures. This approach provides insight into the molecular design and synthesis of Janus-type sensitizers that can be combined with biomolecules, rendering optically active biohybrids.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382221PMC
June 2021

Scaling Up DNA Origami Lattice Assembly.

Chemistry 2021 Jun 4;27(33):8564-8571. Epub 2021 May 4.

Technical and Macromolecular Chemistry, Paderborn University, Warburger Str. 100, 33098, Paderborn, Germany.

The surface-assisted hierarchical assembly of DNA origami nanostructures is a promising route to fabricate regular nanoscale lattices. In this work, the scalability of this approach is explored and the formation of a homogeneous polycrystalline DNA origami lattice at the mica-electrolyte interface over a total surface area of 18.75 cm is demonstrated. The topological analysis of more than 50 individual AFM images recorded at random locations over the sample surface showed only minuscule and random variations in the quality and order of the assembled lattice. The analysis of more than 450 fluorescence microscopy images of a quantum dot-decorated DNA origami lattice further revealed a very homogeneous surface coverage over cm areas with only minor boundary effects at the substrate edges. At total DNA costs of € 0.12 per cm , this large-scale nanopatterning technique holds great promise for the fabrication of functional surfaces.
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http://dx.doi.org/10.1002/chem.202100784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252642PMC
June 2021

A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma.

Small 2021 05 18;17(18):e2007705. Epub 2021 Mar 18.

Department of Chemistry, University of Helsinki, Helsinki, FI-00014, Finland.

Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA-approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium-177 ( Lu) enables simultaneous tracking of tracer accumulation with single-photon emission computed tomography and radiotherapy. Therefore, the codelivery of Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, Lu-labeled CNC NPs loaded with vemurafenib ([ Lu]Lu-CNC-V NPs) is developed and the therapeutic effect in BRAF V600E mutation-harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [ Lu]Lu-CNC-V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [ Lu]Lu-CNC-V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [ Lu]Lu-CNC-V NPs compared to control groups. The enhanced therapeutic efficacy of [ Lu]Lu-CNC-V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP-based drug delivery systems after intravenous administration.
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http://dx.doi.org/10.1002/smll.202007705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175021PMC
May 2021

Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release.

Nucleic Acids Res 2021 04;49(6):3048-3062

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16100, 00076 Aalto, Finland.

Doxorubicin (DOX) is a common drug in cancer chemotherapy, and its high DNA-binding affinity can be harnessed in preparing DOX-loaded DNA nanostructures for targeted delivery and therapeutics. Although DOX has been widely studied, the existing literature of DOX-loaded DNA-carriers remains limited and incoherent. Here, based on an in-depth spectroscopic analysis, we characterize and optimize the DOX loading into different 2D and 3D scaffolded DNA origami nanostructures (DONs). In our experimental conditions, all DONs show similar DOX binding capacities (one DOX molecule per two to three base pairs), and the binding equilibrium is reached within seconds, remarkably faster than previously acknowledged. To characterize drug release profiles, DON degradation and DOX release from the complexes upon DNase I digestion was studied. For the employed DONs, the relative doses (DOX molecules released per unit time) may vary by two orders of magnitude depending on the DON superstructure. In addition, we identify DOX aggregation mechanisms and spectral changes linked to pH, magnesium, and DOX concentration. These features have been largely ignored in experimenting with DNA nanostructures, but are probably the major sources of the incoherence of the experimental results so far. Therefore, we believe this work can act as a guide to tailoring the release profiles and developing better drug delivery systems based on DNA-carriers.
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http://dx.doi.org/10.1093/nar/gkab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034656PMC
April 2021

Engineered protein cages for selective heparin encapsulation.

J Mater Chem B 2021 02 11;9(5):1272-1276. Epub 2021 Jan 11.

Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16100, Aalto FI-00076, Espoo, Finland. and HYBER Centre, Department of Applied Physics, Aalto University, Aalto FI-00076, Finland.

A heparin-specific binding peptide was conjugated to a cowpea chlorotic mottle virus (CCMV) capsid protein, which was subsequently allowed to encapsulate heparin and form capsid-like protein cages. The encapsulation is specific and the capsid-heparin assemblies display negligible hemolytic activity, indicating proper blood compatibility and promising possibilities for heparin antidote applications.
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http://dx.doi.org/10.1039/d0tb02541kDOI Listing
February 2021

Biomolecule-Directed Carbon Nanotube Self-Assembly.

Adv Healthc Mater 2021 01 29;10(1):e2001162. Epub 2020 Oct 29.

Department of Bioproducts and Biosystems, Aalto University, Kemistintie 1, Espoo, 02150, Finland.

The strategy of combining biomolecules and synthetic components to develop biohybrids is becoming increasingly popular for preparing highly customized and biocompatible functional materials. Carbon nanotubes (CNTs) benefit from bioconjugation, allowing their excellent properties to be applied to biomedical applications. This study reviews the state-of-the-art research in biomolecule-CNT conjugates and discusses strategies for their self-assembly into hierarchical structures. The review focuses on various highly ordered structures and the interesting properties resulting from the structural order. Hence, CNTs conjugated with the most relevant biomolecules, such as nucleic acids, peptides, proteins, saccharides, and lipids are discussed. The resulting well-defined composites allow the nanoscale properties of the CNTs to be exploited at the micro- and macroscale, with potential applications in tissue engineering, sensors, and wearable electronics. This review presents the underlying chemistry behind the CNT-based biohybrid materials and discusses the future directions of the field.
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http://dx.doi.org/10.1002/adhm.202001162DOI Listing
January 2021

DNA-Origami-Templated Growth of Multilamellar Lipid Assemblies.

Angew Chem Int Ed Engl 2021 01 9;60(2):827-833. Epub 2020 Nov 9.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, P. O. Box 16100, 00076, Aalto, Finland.

Lipids are important building blocks in cellular compartments, and therefore their self-assembly into well-defined hierarchical structures has gained increasing interest. Cationic lipids and unstructured DNA can co-assemble into highly ordered structures (lipoplexes), but potential applications of lipoplexes are still limited. Using scaffolded DNA origami nanostructures could aid in resolving these drawbacks. Here, we have complexed DNA origami together with a cationic lipid 1,2-dioleoly-3-trimethylammonium-propane (DOTAP) and studied their self-assembly driven by electrostatic and hydrophobic interactions. The results suggest that the DNA origami function as templates for the growth of multilamellar lipid structures and that the DNA origami are embedded in the formed lipid matrix. Furthermore, the lipid encapsulation was found to significantly shield the DNA origami against nuclease digestion. The presented complexation strategy is suitable for a wide range of DNA-based templates and could therefore find uses in construction of cell-membrane-associated components.
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http://dx.doi.org/10.1002/anie.202006044DOI Listing
January 2021

Peptide-guided resiquimod-loaded lignin nanoparticles convert tumor-associated macrophages from M2 to M1 phenotype for enhanced chemotherapy.

Acta Biomater 2021 10 2;133:231-243. Epub 2020 Oct 2.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; Helsinki Institute of Life Science (HiLIFE), University of Helsinki, FI-00014 Helsinki, Finland. Electronic address:

Nanomedicines represent innovative and promising alternative technologies to improve the therapeutic effects of different drugs for cancer ablation. Targeting M2-like tumor-associated macrophages (TAMs) has emerged as a favorable therapeutic approach to fight against cancer through the modulation of the tumor microenvironment. However, the immunomodulatory molecules used for this purpose present side effects upon systemic administration, which limits their clinical translation. Here, the biocompatible lignin polymer is used to prepare lignin nanoparticles (LNPs) that carry a dual agonist of the toll-like receptors TLR7/8 (resiquimod, R848). These LNPs are targeted to the CD206-positive M2-like TAMs using the "mUNO" peptide, in order to revert their pro-tumor phenotype into anti-tumor M1-like macrophages in the tumor microenvironment of an aggressive triple-negative in vivo model of breast cancer. Overall, we show that targeting the resiquimod (R848)-loaded LNPs to the M2-like macrophages, using very low doses of R848, induces a profound shift in the immune cells in the tumor microenvironment towards an anti-tumor immune state, by increasing the representation of M1-like macrophages, cytotoxic T cells, and activated dendritic cells. This effect consequently enhances the anticancer effect of the vinblastine (Vin) when co-administered with R848-loaded LNPs. STATEMENT OF SIGNIFICANCE: Lignin-based nanoparticles (LNPs) were successfully developed to target a potent TLR7/8 agonist (R848) of the tumor microenvironment (TME). This was achieved by targeting the mannose receptor (CD206) on the tumor supportive (M2-like) macrophages with the "mUNO" peptide, to reprogram them into an anti-tumor (M1-like) phenotype for enhanced chemotherapy. LNPs modified the biodistribution of the R848, and enhanced its accumulation and efficacy in shifting the immunological profile of the cells in the TME, which was not achieved by systemic administration of free R848. Moreover, a reduction in the tumor volumes was observed at lower equivalent doses of R848 compared with other studies. Therefore, the co-administration of [email protected] is a promising chemotherapeutic application in aggressive tumors, such as the triple-negative breast cancer.
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http://dx.doi.org/10.1016/j.actbio.2020.09.038DOI Listing
October 2021

Advanced DNA Nanopore Technologies.

ACS Appl Bio Mater 2020 Sep 26;3(9):5606-5619. Epub 2020 Aug 26.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, 00076 Aalto, Finland.

Diverse nanopore-based technologies have substantially expanded the toolbox for label-free single-molecule sensing and sequencing applications. Biological protein pores, lithographically fabricated solid-state and graphene nanopores, and hybrid pores are in widespread use and have proven to be feasible devices for detecting amino acids, polynucleotides, and their specific conformations. However, despite the indisputable and remarkable advantages in technological exploration and commercialization of such equipment, the commonly used methods may lack modularity and specificity in characterization of particular phenomena or in development of nanopore-based devices. In this review, we discuss DNA nanopore techniques that harness the extreme addressability, precision, and modularity of DNA nanostructures that can be incorporated as customized gates or plugs into for example lipid membranes, solid-state pores, and nanocapillaries, thus forming advanced hybrid instruments. In addition to these, there exist a number of diverse DNA-assisted nanopore-based detection and analysis methods. Here, we introduce different types of DNA nanostructure-based pore designs and their intriguing properties as well as summarize the extensive collection of current and future technologies and applications that can be realized through combining DNA nanotechnology with common nanopore approaches.
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http://dx.doi.org/10.1021/acsabm.0c00879DOI Listing
September 2020

Electrostatic Self-Assembly of Protein Cage Arrays.

Methods Mol Biol 2021 ;2208:123-133

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, Aalto, Finland.

Protein and peptide cages are nanoscale containers, which are of particular interest in nanoscience due to their well-defined dimensions and enclosed central cavities that can be filled with material that is protected from the outside environment. Ferritin is a typical example of protein cage, formed by 24 polypeptide chains that self-assemble into a hollow, roughly spherical protein cage with external and internal diameters of approximately 12 nm and 8 nm, respectively. The interior cavity of ferritin provides a unique reaction vessel to carry out reactions separated from the exterior environment. In nature, the cavity is utilized for sequestration and biomineralization to render iron inert and safe by shielding from the external environment. Materials scientists have been inspired by this system and exploited a range of ferritin superfamily proteins as supramolecular templates to encapsulate cargoes ranging from cancer drugs to therapeutic proteins. Interesting possibilities arise if such containers can themselves be arranged into even higher-order structures such as crystalline arrays. Here, we describe how crystalline arrays of negatively charged ferritin protein cages can be built by taking advantage of electrostatic interactions with cationic gold nanoparticles.
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http://dx.doi.org/10.1007/978-1-0716-0928-6_8DOI Listing
March 2021

Robotic DNA Nanostructures.

ACS Synth Biol 2020 08 12;9(8):1923-1940. Epub 2020 Jul 12.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, 00076 Aalto, Finland.

Over the past decade, DNA nanotechnology has spawned a broad variety of functional nanostructures tailored toward the enabled state at which applications are coming increasingly in view. One of the branches of these applications is in synthetic biology, where the intrinsic programmability of the DNA nanostructures may pave the way for smart task-specific molecular robotics. In brief, the synthesis of the user-defined artificial DNA nano-objects is based on employing DNA molecules with custom lengths and sequences as building materials that predictably assemble together by obeying Watson-Crick base pairing rules. The general workflow of creating DNA nanoshapes is getting more and more straightforward, and some objects can be designed automatically from the top down. The versatile DNA nano-objects can serve as synthetic tools at the interface with biology, for example, in therapeutics and diagnostics as dynamic logic-gated nanopills, light-, pH-, and thermally driven devices. Such diverse apparatuses can also serve as optical polarizers, sensors and capsules, autonomous cargo-sorting robots, rotary machines, precision measurement tools, as well as electric and magnetic-field directed robotic arms. In this review, we summarize the recent progress in robotic DNA nanostructures, mechanics, and their various implementations.
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http://dx.doi.org/10.1021/acssynbio.0c00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467825PMC
August 2020

De novo nanomaterial crystals from DNA frameworks.

Nat Mater 2020 07;19(7):706-707

Biohybrid Materials Group, Department of Bioproducts and Biosystems, Aalto University, Aalto, Finland.

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http://dx.doi.org/10.1038/s41563-020-0709-5DOI Listing
July 2020

Phthalocyanine-DNA origami complexes with enhanced stability and optical properties.

Chem Commun (Camb) 2020 Jul;56(53):7341-7344

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, FI-00076 Aalto, Finland. and HYBER Centre, Department of Applied Physics, Aalto University, FI-00076 Aalto, Finland.

In this communication, electrostatically assembled phthalocyanine (Pc)-DNA origami (DO) complexes are formed and their optical properties are demonstrated. The formation of the complex prevents the Pc aggregation, thus yielding an enhanced optical response and photooxidative resilience towards aggregation in biologically relevant media. Simultaneously, the Pc protects the DO against enzymatic digestion. Both features solve previous drawbacks associated with phthalocyanine photosensitizers and DNA nanocarriers. The studied complexes may find use in technologies related to the photogeneration of singlet oxygen, e.g., photocatalysis, diagnositic arrays and photodynamic therapy.
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http://dx.doi.org/10.1039/d0cc01916jDOI Listing
July 2020

Chemical Modification of Reducing End-Groups in Cellulose Nanocrystals.

Angew Chem Int Ed Engl 2021 01 9;60(1):66-87. Epub 2020 Sep 9.

Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16300, FI-00076 Aalto, Espoo, Finland.

Native plant cellulose has an intrinsic supramolecular structure. Consequently, it can be isolated as nanocellulose species, which can be utilized as building blocks for renewable nanomaterials. The structure of cellulose also permits its end-wise modification, i.e., chemical reactions exclusively on one end of a cellulose chain or a nanocellulose particle. The premises for end-wise modification have been known for decades. Nevertheless, different approaches for the reactions have emerged only recently, because of formidable synthetic and analytical challenges associated with the issue, including the adverse reactivity of the cellulose reducing end and the low abundance of newly introduced functionalities. This Review gives a full account of the scientific underpinnings and challenges related to end-wise modification of cellulose nanocrystals. Furthermore, we present how the chemical modification of cellulose nanocrystal ends may be applied to directed assembly, resulting in numerous possibilities for the construction of new materials, such as responsive liquid crystal templates and composites with tailored interactions.
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http://dx.doi.org/10.1002/anie.202002433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821002PMC
January 2021

Increasing Complexity in Wireframe DNA Nanostructures.

Molecules 2020 Apr 16;25(8). Epub 2020 Apr 16.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16100, 00076 Aalto, Finland.

Structural DNA nanotechnology has recently gained significant momentum, as diverse design tools for producing custom DNA shapes have become more and more accessible to numerous laboratories worldwide. Most commonly, researchers are employing a scaffolded DNA origami technique by "sculpting" a desired shape from a given lattice composed of packed adjacent DNA helices. Albeit relatively straightforward to implement, this approach contains its own apparent restrictions. First, the designs are limited to certain lattice types. Second, the long scaffold strand that runs through the entire structure has to be manually routed. Third, the technique does not support trouble-free fabrication of hollow single-layer structures that may have more favorable features and properties compared to objects with closely packed helices, especially in biological research such as drug delivery. In this focused review, we discuss the recent development of wireframe DNA nanostructures-methods relying on meshing and rendering DNA-that may overcome these obstacles. In addition, we describe each available technique and the possible shapes that can be generated. Overall, the remarkable evolution in wireframe DNA structure design methods has not only induced an increase in their complexity and thus expanded the prevalent shape space, but also already reached a state at which the whole design process of a chosen shape can be carried out automatically. We believe that by combining cost-effective biotechnological mass production of DNA strands with top-down processes that decrease human input in the design procedure to minimum, this progress will lead us to a new era of DNA nanotechnology with potential applications coming increasingly into view.
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http://dx.doi.org/10.3390/molecules25081823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221932PMC
April 2020

Agglomeration of Viruses by Cationic Lignin Particles for Facilitated Water Purification.

ACS Sustain Chem Eng 2020 Mar 24;8(10):4167-4177. Epub 2020 Feb 24.

Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16300, FI-00076 Aalto, Espoo, Finland.

Virus contamination of water is a threat to human health in many countries. Current solutions for inactivation of viruses mainly rely on environmentally burdensome chemical oxidation or energy-intensive ultraviolet irradiation, which may create toxic secondary products. Here, we show that renewable plant biomass-sourced colloidal lignin particles (CLPs) can be used as agglomeration agents to facilitate removal of viruses from water. We used dynamic light scattering (DLS), electrophoretic mobility shift assay (EMSA), atomic force microscopy and transmission electron microscopy (AFM, TEM), and UV spectrophotometry to quantify and visualize adherence of cowpea chlorotic mottle viruses (CCMVs) on CLPs. Our results show that CCMVs form agglomerated complexes with CLPs that, unlike pristine virus particles, can be easily removed from water either by filtration or centrifugation. Additionally, cationic particles formed by adsorption of quaternary amine-modified softwood kraft lignin on the CLPs were also evaluated to improve the binding interactions with these anionic viruses. We foresee that due to their moderate production cost, and high availability of lignin as a side-stream from biorefineries, CLPs could be an alternative water pretreatment material in a large variety of systems such as filters, packed columns, or flocculants.
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http://dx.doi.org/10.1021/acssuschemeng.9b06915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147264PMC
March 2020

Serum Albumin-Peptide Conjugates for Simultaneous Heparin Binding and Detection.

ACS Omega 2019 Dec 10;4(26):21891-21899. Epub 2019 Dec 10.

Biohybrid Materials, Department of Bioproducts and Biosystems and HYBER Center of Excellence, Department of Applied Physics, Aalto University, 00076 Aalto, Finland.

Heparin is a polysaccharide-based anticoagulant agent, which is widely used in surgery and blood transfusion. However, overdosage of heparin may cause severe side effects such as bleeding and low blood platelet count. Currently, there is only one clinically licensed antidote for heparin: protamine sulfate, which is known to provoke adverse effects. In this work, we present a stable and biocompatible alternative for protamine sulfate that is based on serum albumin, which is conjugated with a variable number of heparin-binding peptides. The heparin-binding efficiency of the conjugates was evaluated with methylene blue displacement assay, dynamic light scattering, and anti-Xa assay. We found that multivalency of the peptides played a key role in the observed heparin-binding affinity and complex formation. The conjugates had low cytotoxicity and low hemolytic activity, indicating excellent biocompatibility. Furthermore, a sensitive DNA competition assay for heparin detection was developed. The detection limit of heparin was 0.1 IU/mL, which is well below its therapeutic range (0.2-0.4 IU/mL). Such biomolecule-based systems are urgently needed for next-generation biocompatible materials capable of simultaneous heparin binding and sensing.
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http://dx.doi.org/10.1021/acsomega.9b02883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933801PMC
December 2019

Systematic in vitro biocompatibility studies of multimodal cellulose nanocrystal and lignin nanoparticles.

J Biomed Mater Res A 2020 03 13;108(3):770-783. Epub 2019 Dec 13.

Department of Chemistry, Radiochemistry, University of Helsinki, Helsinki, Finland.

Natural biopolymer nanoparticles (NPs), including nanocrystalline cellulose (CNC) and lignin, have shown potential as scaffolds for targeted drug delivery systems due to their wide availability, cost-efficient preparation, and anticipated biocompatibility. As both CNC and lignin can potentially cause complications in cell viability assays because of their ability to scatter the emitted light and absorb the assay reagents, we investigated the response of bioluminescent (CellTiter-Glo®), colorimetric (MTT® and AlamarBlue®), and fluorometric (LIVE/DEAD®) assays for the determination of the biocompatibility of the multimodal CNC and lignin constructs in murine RAW 264.7 macrophages and 4T1 breast adenocarcinoma cell lines. Here, we have developed multimodal CNC and lignin NPs harboring the radiometal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and the fluorescent dye cyanine 5 for the investigation of nanomaterial biodistribution in vivo with nuclear and optical imaging, which were then used as the model CNC and lignin nanosystems in the cell viability assay comparison. CellTiter-Glo® based on the detection of ATP-dependent luminescence in viable cells revealed to be the best assay for both nanoconstructs for its robust linear response to increasing NP concentration and lack of interference from either of the NP types. Both multimodal CNC and lignin NPs displayed low cytotoxicity and favorable interactions with the cell lines, suggesting that they are good candidates for nanosystem development for targeted drug delivery in breast cancer and for theranostic applications. Our results provide useful guidance for cell viability assay compatibility for CNC and lignin NPs and facilitate the future translation of the materials for in vivo applications.
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http://dx.doi.org/10.1002/jbm.a.36856DOI Listing
March 2020

Multimodality labeling strategies for the investigation of nanocrystalline cellulose biodistribution in a mouse model of breast cancer.

Nucl Med Biol 2020 Jan - Feb;80-81:1-12. Epub 2019 Nov 9.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Weill Cornell Medical College, New York, NY, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.

Methods: We have developed a nuclear and fluorescence labeling strategy for nanocrystalline cellulose (CNC), an emerging biomaterial with versatile chemistry and facile preparation from renewable sources. We modified CNC through 1,1'-carbonyldiimidazole (CDI) activation with radiometal chelators desferrioxamine B and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), allowing for the labeling with zirconium-89 (t = 78.41 h) and copper-64 (t = 12.70 h), respectively, for non-invasive positron emission tomography (PET) imaging. The far-red fluorescent dye Cy5 was added for ex vivo optical imaging, microscopy and flow cytometry. The multimodal CNC were evaluated in the syngeneic orthotopic 4T1 tumor model of human stage IV breast cancer.

Results: Modified CNC exhibited low cytotoxicity in RAW 264.7 macrophages over 96 h, and high radiolabel stability in vitro. After systemic administration, radiolabeled CNC were rapidly sequestered to the organs of the reticulo-endothelial system (RES), indicating immune recognition and no passive tumor targeting by the enhanced permeability and retention (EPR) effect. Modification with NOTA was a more favorable strategy in terms of radiolabeling yield, specific radioactivity, and both the radiolabel and dispersion stability in physiological conditions. Flow cytometry analysis of Cy5-positive immune cells from the spleen and tumor corroborated the uptake of CNC to phagocytic cells.

Conclusions: Future studies on the in vivo behavior of CNC should be concentrated on improving the nanomaterial stability and circulation half-life under physiological conditions and optimizing further the labeling yields for the multimodality imaging strategy presented.

Advances In Knowledge: Our studies constitute one of the first accounts of a multimodality nuclear and fluorescent probe for the evaluation of CNC biodistribution in vivo and outline the pitfalls in radiometal labeling strategies for future evaluation of targeted CNC-based drug delivery systems.

Implications For Patient Care: Quantitative and sensitive molecular imaging methods provide information on the structure-activity relationships of the nanomaterial and guide the translation from in vitro models to clinically relevant animal models.
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http://dx.doi.org/10.1016/j.nucmedbio.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375323PMC
January 2021

DNA Origami-Mediated Substrate Nanopatterning of Inorganic Structures for Sensing Applications.

J Vis Exp 2019 09 27(151). Epub 2019 Sep 27.

Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University; HYBER Center of Excellence, Department of Applied Physics, Aalto University;

Structural DNA nanotechnology provides a viable route for building from the bottom-up using DNA as construction material. The most common DNA nanofabrication technique is called DNA origami, and it allows high-throughput synthesis of accurate and highly versatile structures with nanometer-level precision. Here, it is shown how the spatial information of DNA origami can be transferred to metallic nanostructures by combining the bottom-up DNA origami with the conventionally used top-down lithography approaches. This allows fabrication of billions of tiny nanostructures in one step onto selected substrates. The method is demonstrated using bowtie DNA origami to create metallic bowtie-shaped antenna structures on silicon nitride or sapphire substrates. The method relies on the selective growth of a silicon oxide layer on top of the origami deposition substrate, thus resulting in a patterning mask for following lithographic steps. These nanostructure-equipped surfaces can be further used as molecular sensors (e.g., surface-enhanced Raman spectroscopy (SERS)) and in various other optical applications at the visible wavelength range owing to the small feature sizes (sub-10 nm). The technique can be extended to other materials through methodological modifications; therefore, the resulting optically active surfaces may find use in development of metamaterials and metasurfaces.
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http://dx.doi.org/10.3791/60313DOI Listing
September 2019

Lyotropic liquid crystals and linear supramolecular polymers of end-functionalized oligosaccharides.

Chem Commun (Camb) 2019 Sep;55(78):11739-11742

Univ. Grenoble Alpes, CNRS, CERMAV, F-38000 Grenoble, France.

We synthesized permethylated maltoheptaose oligosaccharides, whose both ends, untrivially, have been functionalized with supramolecular binders 2-ureido-4[1H]-pyrimidinones (UPy) after single ring-opening of β-cyclodextrin counterpart. In 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), they show lyotropic liquid crystallinity. In the dried state they allow linear saccharide-based supramolecular polymers by UPy-dimerization.
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http://dx.doi.org/10.1039/c9cc04715hDOI Listing
September 2019

Superstructure-Dependent Loading of DNA Origami Nanostructures with a Groove-Binding Drug.

ACS Omega 2018 Aug 20;3(8):9441-9448. Epub 2018 Aug 20.

Technical and Macromolecular Chemistry, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany.

DNA origami nanostructures are regarded as powerful and versatile vehicles for targeted drug delivery. So far, DNA origami-based drug delivery strategies mostly use intercalation of the therapeutic molecules between the base pairs of the DNA origami's double helices for drug loading. The binding of nonintercalating drugs to DNA origami nanostructures, however, is less studied. Therefore, in this work, we investigate the interaction of the drug methylene blue (MB) with different DNA origami nanostructures under conditions that result in minor groove binding. We observe a noticeable effect of DNA origami superstructure on the binding affinity of MB. In particular, non-B topologies as for instance found in designs using the square lattice with 10.67 bp/turn may result in reduced binding affinity because groove binding efficiency depends on groove dimensions. Also, mechanically flexible DNA origami shapes that are prone to structural fluctuations may exhibit reduced groove binding, even though they are based on the honeycomb lattice with 10.5 bp/turn. This can be attributed to the induction of transient over- and underwound DNA topologies by thermal fluctuations. These issues should thus be considered when designing DNA origami nanostructures for drug delivery applications that employ groove-binding drugs.
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http://dx.doi.org/10.1021/acsomega.8b00934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644410PMC
August 2018

Thermally Induced Reversible Self-Assembly of Apoferritin-Block Copolymer Complexes.

Macromol Rapid Commun 2019 Sep 14;40(18):e1900308. Epub 2019 Aug 14.

Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16100, FI-00076 Aalto, Espoo, Finland.

Protein cages are interesting building blocks for functional supramolecular assemblies. A multi-responsive system composed of apoferritin and thermo-responsive block copolymers complexed through electrostatic interactions is described here. The polymers are linear chains with cationic and thermo-responsive blocks, and both diblock and triblock copolymers are studied. The apoferritin can be reversibly assembled and disassembled in aqueous solutions by altering the temperature and electrolyte concentration of the solutions. The control over the conditions is straightforward and all the components can be recovered, offering a potential alternative for systems requiring chemical or genetic modification of proteins.
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http://dx.doi.org/10.1002/marc.201900308DOI Listing
September 2019

Phthalocyanine-Virus Nanofibers as Heterogeneous Catalysts for Continuous-Flow Photo-Oxidation Processes.

Adv Mater 2019 Sep 8;31(39):e1902582. Epub 2019 Aug 8.

Department of Bioproducts and Biosystems, Aalto University, Kemistintie 1, 02150, Espoo, Finland.

The generation of highly reactive oxygen species (ROS) at room temperature for application in organic synthesis and wastewater treatment represents a great challenge of the current chemical industry. In fact, the development of biodegradable scaffolds to support ROS-generating active sites is an important prerequisite for the production of environmentally benign catalysts. Herein, the electrostatic cocrystallization of a cationic phthalocyanine (Pc) and negatively charged tobacco mosaic virus (TMV) is described, together with the capacity of the resulting crystals to photogenerate ROS. To this end, a novel peripherally crowded zinc Pc (1) is synthesized. With 16 positive charges, this photosensitizer shows no aqueous aggregation, and is able to act as a molecular glue in the unidimensional assembly of TMV. A step-wise decrease of ionic strength in mixtures of both components results in exceptionally long fibers, constituted by hexagonally bundled viruses thoroughly characterized by electron and confocal microscopy. The fibers are able to produce ROS in a proof-of-concept microfluidic device, where they are immobilized and irradiated in several cycles, showing a resilient performance. The bottom-up approach also enables the light-triggered disassembly of fibers after use. This work represents an important example of a biohybrid material with projected application in light-mediated heterogeneous catalysis.
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http://dx.doi.org/10.1002/adma.201902582DOI Listing
September 2019

Real-Time Observation of Superstructure-Dependent DNA Origami Digestion by DNase I Using High-Speed Atomic Force Microscopy.

Chembiochem 2019 11 11;20(22):2818-2823. Epub 2019 Oct 11.

Technical and Macromolecular Chemistry, Paderborn University, Warburger Strasse 100, 33098, Paderborn, Germany.

DNA nanostructures have emerged as intriguing tools for numerous biomedical applications. However, in many of those applications and most notably in drug delivery, their stability and function may be compromised by the biological media. A particularly important issue for medical applications is their interaction with proteins such as endonucleases, which may degrade the well-defined nanoscale shapes. Herein, fundamental insights into this interaction are provided by monitoring DNase I digestion of four structurally distinct DNA origami nanostructures (DONs) in real time and at a single-structure level by using high-speed atomic force microscopy. The effect of the solid-liquid interface on DON digestion is also assessed by comparison with experiments in bulk solution. It is shown that DON digestion is strongly dependent on its superstructure and flexibility and on the local topology of the individual structure.
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http://dx.doi.org/10.1002/cbic.201900369DOI Listing
November 2019
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